Abstract PO026: Bile acid signaling remodels the iCCA immune microenvironment
Authors: María García-Beccaria, Mirian Fernández-Vaquero, Maria Reich, Dominik Pfister, Diran Herebian, Benjamin Goeppert, Darjus Felix Tschaharganeh, Verena Keitel, Mathias Heikenwälder
Journal: Clinical Cancer Research (2022)

Abstract Intrahepatic cholangiocarcinoma (iCCA) primarily arises from the transformation of cholangiocytes (epithelial cells of the bile ducts), is diagnosed at late stage and has a dismal prognosis (average 5-year survival after resection is 32%). An alarming increase in its incidence over the past decades and the scarce treatment options available urges for the development of novel therapeutic strategies to tackle this malignancy. Immunotherapy has had limited success in iCCA. Possible explanations are that iCCA immune microenvironment is poor in CD8+ T cells and rich in immunosuppressive innate immune cells. The immune landscape of iCCA is determined by the aetiology of the liver insult (e.g. viral, cholestatic) and these different iCCA immune landscapes have not yet been characterized. Therefore, in depth studies on the immunobiology of iCCA are essential to develop new immunotherapy strategies where innate immune cells play a prominent role. We hypothesized that bile acids (BA) are a potential, valid therapeutic target for iCCA, as they strongly influence liver immune microenvironment and proliferation. This idea is supported by the fact that BA have an immunomodulatory role through inhibition of NF-KB and reduction of macrophage production of pro-inflammatory cytokines, suppressing cholangiocyte transformation in iCCA. Since BA and derivatives have recently been approved for the treatment of human chronic cholestatic diseases and primary sclerosis cholangitis, but have not yet been tested to treat iCCA, the proposed project might directly offer evidence for a second use of these drugs in patients with iCCA. Using novel preclinical mouse models of iCCA and human iCCA samples, our objective is to develop new therapeutic strategies for iCCA treatment based on BA signalling, that would impair tumour growth and foster the immune response against the tumour. In order to investigate the effects that BA can exert in tumour initiation and development, we adopted a iCCA mouse model based on the hydrodynamic tail-vein delivery of genetic elements specifically in hepatocytes, which differentiate into cholangiocytes and ultimately leads to the development of iCCA, while conserving a competent immune system. We found that by feeding the animals with an endogenous BA-enriched diet (BA diet), we reduced the overall tumor burden and strikingly increased overall survival. The positive response to the BA diet was associated to an inhibition of tumor proliferation and a robust increase in the abundance and activation of inflammatory monocytes and T cells. Our preliminary results indicate that mimicking the effect of BA could represent a novel immunotherapeutic strategy for iCCA. We will present these data as well as ongoing studies including fluorescence-activated cell sorting and single-cell RNA seq sequencing, focused on understanding the cooperation between different immune cell types that foster response against the tumor. Citation Format: María García-Beccaria, Mirian Fernández-Vaquero, Maria Reich, Dominik Pfister, Diran Herebian, Benjamin Goeppert, Darjus Felix Tschaharganeh, Verena Keitel, Mathias Heikenwälder. Bile acid signaling remodels the iCCA immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO026.